Interaction of the Tumor Suppressor p53 With Replication Protein A.
Annual rept. 15 Jul 96-14 Jul 97,
BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA
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Cdc25A, a phosphatase essential for Gl-S transition, associates with, dephosphorylates and activates the cell-cycle regulator cyclin-dependent kinase cdk. p21 is a cdk inhibitor induced by a tumor suppressor such as p53. We identified a cyclin binding motif near the N terminus of Cdc25A that is similar to the cyclin binding Cy motif of p21 family of cdk inhibitors and separate from the catalytic domain. Mutations in this motif disrupt the association of Cdc25A with cdk. A peptide based on the Cy motif of p21 competitively disrupts the association of Cdc25A with cyclin-cdks and inhibits the de-phosphorylation of the kinase. p21 inhibits Cdc25Alcyclin-cdk association and the dephosphorylation of cdk2. Conversely, Cdc25A, which is itself an oncogene up-regulated by the Myc oncogene, associates with cyclin-cdk and protects it from inhibition by p21. These results describe a mechanism by which the Myc- or Cdc25A- induced oncogenic pathways activated frequently in breast cancers are counter-balanced by p53-induced growth-suppressive pathways counterbalance each other by competing for cyclin-cdks.
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